Abstract Context From an energy perspective, the brain is very metabolically demanding. It is well documented that creatine plays a key role in brain bioenergetics. There is some evidence that creatine supplementation can augment brain creatine stores, which could increase memory. Objective A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to determine the effects of creatine supplementation on memory performance in healthy humans. Data Sources The literature was searched through the PubMed, Web of Science, Cochrane Library, and Scopus databases from inception until September 2021. Data Extraction Twenty-three eligible RCTs were initially identified. Ten RCTs examining the effect of creatine supplementation compared with placebo on measures of memory in healthy individuals met the inclusion criteria for systematic review, 8 of which were included in the meta-analysis. Data Analysis Overall, creatine supplementation improved measures of memory compared with placebo (standard mean difference [SMD] = 0.29, 95%CI, 0.04–0.53; I2 = 66%; P = 0.02). Subgroup analyses revealed a significant improvement in memory in older adults (66–76 years) (SMD = 0.88; 95%CI, 0.22–1.55; I2 = 83%; P = 0.009) compared with their younger counterparts (11–31 years) (SMD = 0.03; 95%CI, −0.14 to 0.20; I2 = 0%; P = 0.72). Creatine dose (≈ 2.2–20 g/d), duration of intervention (5 days to 24 weeks), sex, or geographical origin did not influence the findings. Conclusion Creatine supplementation enhanced measures of memory performance in healthy individuals, especially in older adults (66–76 years). Systematic Review Registration PROSPERO registration no. 42021281027.